Molecular Design International, Inc. (MDI) has designed and synthesized three synthetic retinoids based on the removal of the free carboxylic acid proton and replacement with an ester moiety in 14-all trans retinoic acid (RA), 13-cis retinoic acid (13-cis RA) and 9-cis retinoic acid (9-cis RA), respectively. Based on our preliminary studies in the rhinomouse model, one of these agents (MDI-301; the 9-cis RA derivative) has activity in models that predict efficacy in treatment of acne and efficacy in dermal repair. At the same time, this molecule appears to be significantly less irritating than the natural retinoids. The primary goal of the Phase I studies is to extend these preliminary findings with MDI-301 from animal models to preclinical models with human organ-cultured skin. Another important but ancillary goal of the Phase I research is to begin elucidating the cellular and molecular basis for retinoid irritation in the skin. The use of a non-irritating synthetic agent in conjunction with the naturally-occurring analogues should provide significant insight into the mechanisms by which the naturally occurring agents produce irritation. To achieve the overall objectives of the Phase I studies, we will compare MDI-301 with RA for efficacy (i.e., increased epidermal and dermal proliferation, increased procollagen production and decreased elaboration of matrix metalloproteinases) and for induction of irritation in organ cultures of human skin. Finally, we will utilize the rhinomouse model to examine MDI-403 (13-cis RA derivative) and MDI-101 (RA derivative) for i) reduction of superficial cysts (utriculi) formation, ii) induction of dermal repair and iii) induction of skin irritation. If MDI-301 or either of the other two agents proves to have efficacy without producing irritation, they will provide strong candidates for replacement of currently used retinoids in topical applications.